Dopamine D4 ligands related to the compounds of the invention are known from WO 98/28293. The indane and dihydroindole derivatives disclosed therein have the general formula
wherein A is an indole and Y is a group completing an indane, or a dihydroindole and the other substituents are as defined in the application.
WO 00/23441 discloses compounds of the general formula
wherein the substituents R1, R2, R3, m, n and p are as defined in the application. The compounds are said to show high affinity to dopamine D2 receptors and are also said to be serotonin reuptake inhibitors. The compounds are claimed to be useful for the treatment of schizophrenia and other psychotic disorders.
Other compounds structurally related to the compounds of the invention are described in WO 99/58525. The compounds disclosed therein are said to be 5-HT2A ligands and serotonin reuptake inhibitors and have the general formula
wherein the substituents are as defined in the application. The compounds are said to be useful for the treatment of schizophrenia.
WO 00/31074 relates to compounds having the formula
wherein X is CO or SO2 and Y is N—R4 or CR4R5 and the substitutents are as described in the application. The compounds are said to be active at the 5-HT2A receptor, to have 5-HT reuptake inhibiting activity and to enhance 5-HT release.
The applications, WO 94/18197, EP 329168, WO 93/16073, EP 732332, WO98/37893 and WO 95/11680, disclose dopamine D4 ligands, which, like the compounds of the present invention, are substituted tetrahydroquinolinone and tetrahydroisoquinolinone derivatives. However, these compounds do not contain an indole as the compounds of the invention. The compounds are said to be dopamine D4 ligands useful as antipsychotics. The compounds of WO 93/16073 are also claimed to have antagonistic activity at 5-HT2 receptors.
Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effect of neuroleptics. The side effects of neuroleptic drugs, which primarily exert their effect via antagonism of D2 receptors, are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors, and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526 and Sanner Exp. Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958), have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent antagonist (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84).
Further, evidence for a genetic association between the “primarily inattentive” subtype of ADHD and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol. Psychiat. 2000, 5, 531-536). This clearly indicates a link between the dopamine D4 receptor and ADHD, and ligands affecting this receptor may be useful for the treatment of this particular disorder
Dopamine D3 receptors also belong to the dopamine D2 subfamily of receptors, and they are preferentially located in the limbic brain regions (Sokoloff et al. Nature 1990, 347, 146-151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Willner Int. Clinical Psychopharmacology 1997, 12, 297-308). Furthermore, an elevation of the level of D3 receptors in the limbic part of schizophrenic brains has been reported (Gurevich et al. Arch Gen Psychiatry 1997, 54, 225-32). Therefore, D3 receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D2 receptors (Shafer et al. Psychopharmacology 1998, 135, 1-16 and Schwartz et al. Brain Research Reviews 2000, 31, 277-287).
Moreover, D3 receptor blockade results in a slight stimulation in the prefrontal cortex (Merchant et al. Cerebral Cortex 1996, 6, 561-570), which could be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, D3 antagonists can reverse D2 antagonist-induced EPS (Millan et al. Eur. J Pharmacol. 1997, 321, R7-R9) and do not cause changes in prolactin (Reavill et al. J. Pharmacol. Exp. Ther. 2000, 294, 1154-1165). Consequently, D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al. Current Pharmaceutical Design 1997, 3, 391-404).
Various effects are known with respect to compounds, which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have been reported, e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; “Migraine—Current trends in research and treatment”; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al. Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).
Some clinical studies implicate the 5-HT2 receptor subtype in aggressive behaviour. Further, atypical serotonin-dopamine antagonist neuroleptics have 5-HT2 receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents. 1998, 8(4), 350-351).
Recently, evidence has also accumulated which support the rationale for selective 5-HT2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22-24).
Compounds which are 5-HT reuptake inhibitors are well-known antidepressant drugs.
5-HT2C ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT2C receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DK00/00671).
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients. Compounds with combined effect at the dopamine D4 receptor and the 5-HT2A receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia, and the benefit of effect on depressive and anxiety symptoms. Furthermore, dopamine D3 antagonistic properties of an antipsychotic drug may reduce the negative symptoms and cognitive deficits of schizophrenia and result in an improved side effect profile.